Chiral pyrrolidine core compounds en route to inhibitors of nitric oxide synthase

ABSTRACT

Diastereomeric pyrrolidine compounds and methods of preparation, as can be used en route to the preparation of a range of nitric oxide synthase inhibitors.

This application claims priority benefit from application Ser. No.61/216,364 filed May 15, 2009, the entirety of which is incorporatedherein by reference.

This invention was made with government support under grant No. R01GM049725 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Selective inhibition of the neuronal isozyme of nitric oxide synthase(nNOS) has attracted significant interest as a novel strategy indeveloping therapeutics for the treatment of neurodegenerative diseasesincluding Parkinson's disease, Alzheimer's disease, and Huntington'sdisease. Efforts to design nNOS selective inhibitors include developmentof a stereospecific pyrrolidine-based inhibitor (1, FIG. 1), whichshowed great potency (K_(i)=5 nM) and extremely high selectivity fornNOS over closely related isoforms, endothelial NOS (eNOS, 3800 fold)and inducible NOS (iNOS, 1200 fold). Animal tests demonstrated that 1could lead to a remarkable reduction in neurological damage to rabbitfetuses under hypoxic conditions, making 1 a strong candidate as a newdrug for the treatment of neurodegenerative diseases.

Despite these and other discoveries, current and future research relatedto 1 is somewhat hindered by a complicated synthesis. In particular, thechiral pyrrolidine intermediate compound 2 (FIG. 1), achieved by aseven-step procedure of the prior art, is disadvantaged by expensivestarting material(s), difficult chromatographic purification(s), and lowoverall yield (<2%). Moreover, utilization of racemic starting materialsrequires extra chiral resolution step(s) using either HPLC or chiralauxiliaries, which dramatically reduce the yield and efficiency.Therefore, the development of an efficient route to chiral core compound2 remains an ongoing concern, the absence of which will continue toimpede future investigations of inhibitor 1.

SUMMARY OF THE INVENTION

In light of the foregoing, it is an object of the present invention toprovide a diastereoselective synthesis of pyrrolidine core compounds,thereby overcoming various deficiencies and shortcomings of the priorart, including those outlined above. It will be understood by thoseskilled in the art that one or more aspects of this invention can meetcertain objectives, while one or more other aspects can meet certainother objectives. Each objective may not apply equally in all itsrespects, to every aspect of this invention. As such, the followingobjects can be viewed in the alternative with respect to any one aspectof this invention.

It can be an object of the present invention to provide acost-effective, efficient route to chiral pyrrolidine compounds of thesort described above and illustrated elsewhere herein.

It can be another object of the present invention to provide suchcompounds without use of racemic starting materials and/or difficultresolutions.

It can be another object of the present invention, alone or inconjunction with one or more of the preceding objectives, to provide asynthetic approach to a diastereomeric pyrrolidine core compound, enroute to a range of NOS inhibitor compounds, including selective nNOSinhibitor compounds.

Other objects, features, benefits and advantages of the presentinvention will be apparent from this summary and the followingdescriptions of certain embodiments, and will be readily apparent tothose skilled in the art of organic synthesis. Such objects, features,benefits and advantages will be apparent from the above as taken intoconjunction with the accompanying examples, data, figures and allreasonable inferences to be drawn therefrom, alone or with considerationof the references incorporated herein.

In part, the present invention can be directed to a method of preparinga chiral pyrrolidine core compound. Such a method can comprise providinga dialkyl (R)-(+)-malate or a dialkyl (S)-(−)-malate; diastereoselectivealkylation of such a malate with a haloalkylheterocyclic compound toprovide a corresponding alkyl-substituted malate; reduction of one estergroup to provide a half-ester half-aldehyde intermediate; reductiveamination of the aldehyde group of such an intermediate; reduction ofthe ester group of such an intermediate, to provide an alcohol; andderivatization of the alcohol moiety and subsequent intramolecularcyclization, to provide a pyrrolidine core compound. Optionally, such analkyl-substituted malate can undergo allylation. In certain suchembodiments, subsequent oxidation and reductive amination with anethanamine can provide a corresponding NOS inhibitor compound.

In certain non-limiting embodiments, such a method can utilize an(R)-stereoisomer as a chiral starting material. An (S)-stereoisomer canbe used in certain other embodiments. Regardless, various dialkyl malatestarting materials are available, either commercially or by syntheticprocedures well known to those skilled in the art. In particular,diisopropyl and dimethyl malate stereoisomers can be used with goodeffect. Likewise, with respect to an alkylheterocyclic startingmaterial, a pyridine compound (e.g., without limitation, ahaloalkylpyridine compound) can be substituted as would be understood bythose skilled in the art, such substitution limited only by subsequentmalate alkylation, as illustrated below. In certain non-limitingembodiments, such a heterocyclic and/or pyridine compound can comprisean amino group or a protected amino group (e.g., without limitation,with 2,5-hexanedione, to provide the corresponding 2,5-dimethylpyrroleprotecting group). Regardless, in certain embodiments hexamethyldisilazide can be employed to effect alkylation, but various other basescan be utilized as would be understood by those skilled in the art. Incertain such embodiments, reducing the amount of a 2-bromomethylpyridinestarting material to less than stoichiometric can be used to improveyield of the resulting alkylation product.

Regardless, ester and subsequent aldehyde reduction can be achievedusing various synthetic techniques understood by those skilled in theart. While the use of certain reagents is illustrated, various otherreagents can be utilized, such reagents limited only by subsequentchemistry and modification of the sort described herein. For instance,without limitation, while reductive amination is illustrated usingbenzylamine, various other substituted amines can be employed, suchcompounds limited only by production of the corresponding pyrrolidinecore compound, deprotection and/or subsequent chemistry thereon.Likewise, while certain embodiments provide mesylation and subsequentintramolecular cyclization, it would be known to those skilled in theart that various other alcohol derivatives can be utilized underappropriate reaction conditions to achieve similar or comparable effect.

In part, the present invention can also be directed to a method of usingdiastereoselective alkylation to provide a diastereomeric pyrrolidinecore compound. Such a method can comprise providing a Frater-Seebachdiastereoselective alkylation product of a dialkyl (R)-(+)-malate or adialkyl (S)-(−)-malate and, for instance, a bromomethylpyridine startingmaterial; reduction of an ester group of such an alkylation product, toprovide a half-ester half-aldehyde intermediate; reductive amination ofthe aldehyde group of such an intermediate and reduction of the estergroup of such an intermediate; and derivatization and subsequentintramolecular cyclization, to provide a corresponding, diastereomericpyrrolidine core compound.

In certain non-limiting embodiments, such an alkylation product can beallylated, as illustrated below. In various other embodiments, thehydroxy group of such a malate starting material can be protected orotherwise derivatized, as would be understood by those skilled in theart, such protection or derivatization limited only by subsequentreaction or modification of the resulting pyrrolidine core compound enroute to a specific NOS inhibitor. Regardless, in various otherembodiments, with reductive amination of such a half-ester half-aldehydeintermediate, subsequent ester reduction can be achieved withoutintermediate isolation or purification.

Accordingly, the present invention can be directed to a compound of aformula

wherein R₁ can be selected from C(O)OR′₁, CH₂OH and CH₂SO₃CH₃ moieties,where R′₁ can be selected from the C₁-about C₆ alkyl and C₁-about C₆substituted alkyl moieties; R₂ can be selected from C₁-about C₆ alkyland C₁-about C₆ substituted alkyl moieties; R₃ can be selected from Hand alkyl moieties; and R₄ can be selected from H, amino and protectedamino moieties, and salts, hydrates and/or solvates of such a compound.In certain non-limiting embodiments, R₃ can be an alkyl moiety, and R₄can independently be a 2,5-dimethylpyrrol-1-yl moiety. When present as asalt, such a compound can be either partially or fully protonated. Incertain such embodiments, a counter ion can be a conjugate base of aprotic acid. Regardless, such a compound can be selected from (2S,3R)and (2R,3R) diastereomers and a mixture thereof.

In certain such embodiments, R₂ can be a benzyl moiety. Optionally, R₁can be a CH₂SO₃CH₃ moiety; that is, such a compound can be mesylated topromote intramolecular cyclization. The allyl moiety of the resultingpyrrolidine compound can be oxidized to an aldehyde group, thenreductively aminated with an ethanamine en route to a corresponding NOSinhibitor compound of the sort described in co-pending application Ser.No. 12/693,196 filed Jan. 25, 2010, the entirety of which isincorporated herein by reference.

More broadly, the present invention can be directed to the preparationof a range of chiral pyrrolidine core compounds. Such a method cancomprise providing a diastereoselective alkylation product of a chiraldialkyl malate and a haloalkyl-substituted heterocycle startingmaterial. Subsequent steps of such a method can be as described above orillustrated elsewhere, herein. While the present invention can beillustrated in the context of a 4-methylpyridine moiety conjugated witha pyrrolidine core, it will be understood by those skilled in the artthat conjugation via malate alkylation can be achieved with variousother haloalkyl-pyridine and other haloalkylheterocyclic moieties. Forexample, without limitation, various other heterocyclic moietiesincluding but not limited to substituted and unsubstituted thiazine,oxazine, pyrazine, oxazole and imidazole moieties—regardless of thepresence or protection of an amino substituent—are described in U.S.Pat. No. 7,470,790 issued Dec. 30, 2008 and co-pending application Ser.No. 11/906,283 filed Oct. 1, 2007, in the context of substructure I asdiscussed more fully therein, each of which is incorporated herein byreference in its entirety. The corresponding chiral pyrrolidine corecompounds can be prepared using synthetic techniques of the sortdescribed herein or straight forward modifications thereof, as would beunderstood by those skilled in the art and made aware of this invention.Such heterocycle-conjugated compounds, analogous to core compound 2, canbe used en route to NOS inhibitors, including selective nNOS inhibitors,of the sort described in the aforementioned incorporated references.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Certain embodiments of this invention illustrate the development of aconcise stereospecific synthesis of 2. An initial plan was to use adisubstitution reaction on dimesylate 3 with benzylamine (Scheme 1).Dimesylated compound 3 could be derived from dialkyl malate (4) using asequential allylation-reduction procedure. Stereospecific compound 4could be achieved by the diastereoselective alkylation protocoldeveloped by Frater et al. and Seebach et al. using dialkyl(R)-(+)-malate (5) and2-(bromomethyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (6) asstarting materials. (See, Frater, G.; Müller, U.; Günther, W.Tetrahedron 1984, 40, 1269; and Seebach, D.; Aebi, J.; Wasmuth, D. Org.Syn. Coll. 1985, 7, 153.)

The synthesis of 6 began with 2-aminopyridine (7, Scheme 2). The aminofunctional group of 7 was protected using 2,5-hexanedione in thepresence of p-toluenesulfonic acid (p-TsOH) to give 8 in high yields.The 2,5-dimethylpyrrole protecting group was selected for two reasons.First, this protecting group is known to be stable under a variety ofreaction conditions and can be easily removed under mild conditions.Second, the electron-donating property of the 2,5-dimethylpyrrole groupincreases the chelating ability of the pyridine nitrogen to the lithiumion, which favors regioselective deprotonation of the 2-methyl group onthe pyridine ring. 8 was treated with n-BuLi at 0° C., and the resultinganion was quenched with chlorotrimethylsilane (TMSCl) at the sametemperature to generate 9 exclusively. Finally, 9 was allowed to reactwith 1,2-dibromotetrafluoroethane in the presence of CsF to provide 6 inquantitative yields.

Next, optimization of the conditions for the Frater-Seebach alkylationwas investigated (Table 1). When using lithium diisopropylamide (LDA) asthe base, only a trace amount of product was isolated using either 5a or5b as the starting material (Table 1, entries 1 and 2). With lithiumhexamethyldisilazide (LHMDS) as the base however, products 4a and 4bcould be isolated in 23% and 56% yield, respectively, with highdiastereoselectivity (Table 1, entries 3 and 4). Yield was improved to85% by changing the ratio between 5b and 6 (Table 1, entries 5 to 7).

TABLE 1 Frater-Seebach Diastereoselective Alkylation.

entry R base 6 (eq.) yield^(b) (%) trans/cis^(c) 1 Me LDA 1.0 <2 2 i-PrLDA 1.0 <2 3 Me LHMDS 1.0 23  8:1 4 i-Pr LHMDS 1.0 56 >15:1 5 i-Pr LHMDS0.75 70 >15:1 6 i-Pr LHMDS 0.5 77 >15:1 7 i-Pr LHMDS 0.33 85 >15:1^(a)General experimental conditions: 2 equiv of base was added to 1equiv of 5 at −78° C., then the reaction temperature was raised to 0° C.and remained for 20 min. The reaction was cooled to −78° C. and compound6 was added. ^(b)Isolated yields. ^(c)Determined by 1H NMR.

Allylation of 4b via NaH and allylbromide yielded 10, which was reducedusing LiAlH₄ to generate diol 11 in excellent yields (Scheme 3). When 11was submitted to a variety of mesylation conditions, however, the onlyproducts that could be detected were compounds 13 and 14, derived byintramolecular cyclizations from either the pyridinyl nitrogen atom (13)or the hydroxyl oxygen atom (14), respectively.

To avoid these intrinsic problems, a new synthetic route was designedaround intermediate dialdehyde 15 (Scheme 4), which can undergo asingle-step reductive amination reaction to provide 2. (See, Vysko{hacekover (c)}il, {hacek over (S)}; Jaracz, S.; Smr{hacek over (c)}ina, M.;{hacek over (S)}tícha, M.; Hanu{hacek over (s)}, V.; Polá{hacek over(s)}ek, M.; Ko{hacek over (c)}ovský., P. J. Org. Chem. 1998, 63, 7727;and Marsault, E.; Benakli, K.; Beaubien, S.; Saint-Louis, C.; Dėziel,R.; Fraser, G. Bioorg. Med. Chem. Lett. 2007, 17, 4187.) It was hopedthat under reductive conditions, dialdehyde 15 could be generated fromdiisopropylester 10.

The results of the Dibal-H reduction of 10 are summarized in Table 2.When 3.5 equiv of Dibal-H were used at −78° C. for 2 h (Table 2, entry1), three different products, aldehyde 16, alcohol 17, and semi-acetal18, were isolated. 18 was the major product, but no dialdehyde 15 wasdetected. Next, fewer equiv of the reducing reagent were used. The datashowed that either only aldehyde 16 (Table 2, entry 2), or 16 and 17(Table 2, entries 3 and 4) were isolated from the reaction without anyevidence of dialdehyde 15 formation. Additional reduction of aldehyde 16using Dibal-H (1 equiv) yielded only alcohol 17, which, together withthe previous Dibal-H reduction data, confirmed that dialdehyde 15 couldnot be generated by reduction of 10.

TABLE 2 Results of Dibal-H Reduction

Dibal-H yield^(b) (%) entry (equiv) time (h) 10 16 17 18 1 3.5 2 0 5 1580 2 2.0 2 80 20 0 0 3 2.0 7 28 62 10 0 4 1.5 7 26 70 4 0 ^(a)Generalexperimental conditions: 1 equiv of 10 was added Dibal-H at −78° C.^(b)Isolated yields.

Even though dialdehyde 15 was not produced, aldehyde 16 was isolated ingood yields after simple optimizations (Table 2, entry 4). Amine 20 wasprepared from 16 in the hope that the additional amino group of 20 wouldcompete with the aminopyridine nitrogen for cyclization, thus preventingthe formation of 13 and yielding the desired compound 2.

As shown in Scheme 5, reductive amination of 16 with benzylamine in thepresence of NaHB(OAc)₃ provided amine 19 in excellent yields withcomplete retention of stereochemistry. Next, the isopropyl ester of 19was reduced with LiAlH₄ to generate primary alcohol 20 in good yields. Aone-pot procedure without purification of 19 improved the overall yield(83%).

Finally, compound 20 was treated with methylsulfonyl chloride (MsCl) inthe presence of TEA. The intramolecular cyclization from thebenzyl-protected amine is so fast that 2 was obtained in quantitativeyields without formation of any other side products.

As shown, above, this invention provides an efficient and highlydiastereoselective synthesis of the chiral pyrrolidine building block(2) for a novel nNOS inhibitor (1), employing a Frater-Seebach typealkylation and a fast intramolecular cyclization, to avoid or minimizeunwanted cyclization by the pyridine nitrogen. While the precedingdiscussion and following examples illustrate synthesis of a(3R,4R)-diastereomer from an (R)-(+)-malate, a (3S,4S)-diastereomer canbe prepared analogously from a corresponding (S)-(−)-malate.

EXAMPLES OF THE INVENTION

The following non-limiting examples and data illustrate various aspectsand features relating to the methods of the present invention, includingthe preparation of diastereomeric pyrrolidine compounds, as areavailable through the synthetic methodologies described herein. Incomparison with the prior art, the present methods provide results anddata which are surprising, unexpected and contrary thereto. While theutility of this invention is illustrated through the use of severalstarting materials and substituents thereof, reactants and substituentsthereof, reagents and reaction conditions which can be used therewith,it will be understood by those skilled in the art that comparableresults are obtainable with various other starting materials and/orsubstituents (e.g., other heterocyclic and substituted heterocyclicstarting materials), reactants and/or substituents, reagents andreaction conditions, as are commensurate with the scope of thisinvention.

General Methods. All experiments were conducted under anhydrousconditions in an atmosphere of argon, using flame-dried apparatus andemploying standard techniques in handling air-sensitive materials. Allsolvents were distilled and stored under an argon or nitrogen atmospherebefore using. All reagents were used as received. Aqueous solutions ofsodium bicarbonate, sodium chloride (brine), and ammonium chloride weresaturated. Analytical thin layer chromatography was visualized byultraviolet, ninhydrin, or phosphomolybdic acid (PMA). Flash columnchromatography was carried out under a positive pressure of nitrogen. ¹HNMR spectra were recorded on 500 MHz spectrometers. Data are presentedas follows: chemical shift (in ppm on the δ scale relative to δ=0.00 ppmfor the protons in TMS), integration, multiplicity (s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, br=broad), couplingconstant (J/Hz). Coupling constants were taken directly from the spectraand are uncorrected. ¹³C NMR spectra were recorded at 125 MHz, and allchemical shift values are reported in ppm on the δ scale, with aninternal reference of δ 77.0 or 49.0 for CDCl₃ or MeOD, respectively.High-resolution mass spectra were measured on liquidchromatography/time-of-flight mass spectrometry (LC-TOF).

Preparation and Characterization of Compounds

Example 1

2-(2,5-Dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyridine (8) To a solutionof 4,6-dimethyl-2-aminopyridine (7, 12.2 g, 100 mmol) in toluene (100mL) was added acetonylacetone (12.3 mL, 105 mmol) and p-TsOH (190 mg,1.0 mmol). The reaction mixture was heated in a Dean-Stark apparatusunder reflux for 6 h. After cooling to room temperature, the mixture wasconcentrated with a rotary evaporator, and the resulting brown oil waspurified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) togive 8 (18.2 g, 91 mmol, 91%) as a pale yellow solid: ¹H NMR (500 MHz,CDCl₃) δ 2.13 (s, 6H), 2.40 (s, 3H), 2.56 (s, 3H), 5.88 (s, 2H), 6.85(s, 1H), 7.00 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.4, 21.2, 24.4,106.8, 119.9, 123.1, 128.6, 149.6, 151.7, 158.4; LCQ-MS (M+H⁺) calcd forC₁₃H₁₇N₂ 201. found 201; LC-TOF-MS (M+H⁺) calcd for C₁₃H₁₇N₂ 201.13917.found 201.13881.

Example 2

2-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methyl-6-((trimethylsilyl)methyl)pyridine(9). To a solution of 8 (6.0 g, 30 mmol) in THF (100 mL) at 0° C. wasadded n-BuLi (1.6 M in hexanes, 21 mL, 33 mmol). The solution turneddark red during the addition. After stirring at the same temperature foran additional 2 h, chlorotrimethylsilane (4.2 mL, 33 mmol) was addeddropwise to the reaction mixture. The reaction was warmed to roomtemperature and allowed to stir for an additional 1 h. The resultingbright yellow slurry was partitioned between EtOAc (200 mL) and H₂O (100mL). The organic layer was washed with brine (100 mL), dried over NaSO₄,and concentrated. The crude product was purified by flash columnchromatography (EtOAc/hexanes, 1:19-1:9) to give 9 (7.7 g, 28.5 mmol,95%) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 9H), 2.13(s, 6H), 2.39 (s, 3H), 2.41 (s, 3H), 5.89 (s, 2H), 6.78 (s, 1H), 6.85(s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ −1.5, 13.1, 20.9, 29.8, 106.2,118.7, 121.9, 128.3, 148.8, 151.5, 161.4; LCQ-MS (M+H⁺) calcd forC₁₆H₂₅N₂Si 273. found 273; LC-TOF-MS (M+H⁺) calcd for C₁₆H₂₅N₂Si273.17870. found 273.17735.

Example 3

2-(Bromomethyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (6). Toa solution of 9 (5.6 g, 21 mmol) in DMF (100 mL) was added1,2-dibromotetrafluoroethane (10 g, 42 mmol) and CsF (6.4 g, 42 mmol).The reaction was allowed to stir at room temperature for 3 h, and theresulting purple solution was concentrated and loaded directly on flashcolumn chromatography (EtOAc/hexanes, 1:19-1:9) to give 6 (5.7 g, 20.8mmol, 99%) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 2.19 (s, 6H),2.47 (s, 3H), 4.56 (s, 2H), 5.93 (s, 2H), 7.01 (s, 1H), 7.30 (s, 1H);¹³C NMR (125 MHz, CDCl₃) δ 13.3, 21.1, 33.5, 107.1, 121.8, 122.9, 128.5,150.7, 151.7, 156.3; LCQ-MS (M+H⁺) calcd for C₁₃H₁₆BrN₂ 279. found 279;LC-TOF-MS (M+H⁺) calcd for C₁₃H₁₆BrN₂ 279.04969. found 279.04963.

Example 4

(2S,3R)-dimethyl246-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-3-hydroxysuccinate(4a). Dimethyl ester 4a was synthesized using a similar procedure as for4b (23%): ¹H NMR (500 MHz, CDCl₃) δ 2.11 (s, 6H), 2.40 (s, 3H),3.13-3.17 (dd, J=8.5, 14.5 Hz, 1H), 3.38-3.42 (m, 2H), 3.64 (s, 3H),3.79-3.82 (m, 4H), 4.19 (br s, 1H), 5.89 (s, 2H), 6.89 (s, 1H), 7.09 (s,1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.4, 21.2, 35.7, 38.7, 48.0, 52.2,53.1, 67.5, 70.6, 107.0, 120.8, 123.9, 128.7, 150.2, 151.9, 158.4,171.3, 172.5, 174.0; LCQ-MS (M+H⁺) calcd for C₁₉H₂₅N₂O₅ 361. found 361;LC-TOF-MS (M+H⁺) calcd for C₁₉H₂₅N₂O₅ 361.17635. found 361.17630.

Example 5

(2S,3R)-Diisopropyl2-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-3-hydroxysuccinate(4b). To a dry flask containing THF (20 mL) at −78° C. was added freshLHMDS (1.0 M in THF, 10 mL, 10 mmol). After 10 min, a solution ofdiisopropyl (R)-(+)-malate (5b, 1008 μL, 4.88 mmol) was added dropwiseas a solution in THF (5 mL) through a cannula. The reaction was stirredat the same temperature for 10 min then transferred to an ice-bath (0°C.) for 30 min. The reaction was cooled to −78° C. again and 6 (1017 mg,3.66 mmol) was added slowly (1 drop/sec) as a solution in THF (5 mL)through a cannula. The color of the reaction mixture turned lightpurple. The reaction was maintained at −78° C. for an additional 30 minthen transferred to an ice-bath and slowly warm to room temperature.After 2 h, the reaction was quenched with NH₄Cl (1 mL) then partitionedbetween EtOAc (200 mL) and saturated NH₄Cl (150 mL). The inorganic layerwas extracted with EtOAc (150 mL). The combined organic layer was washedby H₂O (100 mL), brine (100 mL), dried over Na₂SO₄, and concentrated.The crude yellow oil was purified by flash column chromatography(EtOAc/hexanes, 1:9-1:4) to give 4b (1.76 g, 2.56 mmol, 70%) as a paleyellow oil (without detection of any cis-isomer): ¹H NMR (500 MHz,CDCl₃) δ 1.14-1.15 (d, J=6.5 Hz, 3H), 1.17-1.18 (d, J=6.0 Hz, 3H),1.25-1.26 (d, J=6.5 Hz, 3H), 1.29-1.30 (d, J=6.0 Hz, 3H), 2.13 (s, 6H),2.41 (s, 3H), 3.10-3.15 (dd, J=8.5, 14.0 Hz, 1H), 3.34-3.40 (m, 2H),3.72-3.76 (dt, J=2.5, 8.0 Hz, 1H), 4.07-4.09 (dd, J=2.5, 7.0 Hz, 1H),4.96-5.01 (m, 1H), 5.09-5.15 (m, 1H), 5.90 (s, 2H), 6.89 (s, 1H), 7.10(s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.5, 21.2, 21.8, 21.9, 22.0, 36.1,48.0, 68.8, 70.1, 70.6, 107.0, 120.7, 124.1, 128.7, 150.1, 158.7, 171.5,173.4; LCQ-MS (M+H⁺) calcd for C₂₃H₃₃N₂O₅ 417. found 417; LC-TOF-MS(M+H⁺) calcd for C₂₃H₃₃N₂O₅ 417.23895. found 417.23834.

Example 6

(2R,3S)-Diisopropyl2-(allyloxy)-3-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)succinate(10). To a solution of alcohol 4b (300 mg, 0.72 mmol) in THF (10 mL) at0° C. was added NaH (60% in mineral oil, 35 mg, 0.87 mmol). The mixturewas allowed to stir at 0° C. for an additional 30 min then allyl bromide(93 μL, 1.08 mmol) was added dropwise. The reaction was allowed to warmto room temperature and maintained for an additional 6 h. The reactionwas quenched with saturated NH₄Cl (1 mL) and partitioned between EtOAc(100 mL) and H₂O (50 mL). The organic layer was washed with brine (50mL) and dried over Na₂SO₄. The solvent was removed by rotaryevaporation, the resulting brown oil was purified by flash columnchromatography (EtOAc/hexanes, 1:9-1:1) to give 10 (316 mg, 0.69 mmol,97%) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 1.07-1.09 (d, J=6.0Hz, 3H), 1.16-1.19 (d, J=6.0 Hz, 3H), 1.25-1.35 (m, 6H), 2.13 (s, 6H),2.39 (s, 3H), 3.01-3.05 (dd, J=5.5, 15.5 Hz, 1H), 3.20-3.25 (dd, J=9.5,15.0 Hz, 1H), 3.67-3.68 (dd, J=3.0, 4.5 Hz, 1H), 3.89-3.94 (dd, J=7.0,13.0 Hz, 1H), 4.02-4.03 (d, J=5.0 Hz, 1H), 4.24-4.28 (dd, J=4.5, 12.0Hz, 1H), 4.93-4.96 (m, 1H), 4.97-5.17 (m, 1H), 5.17-5.19 (d, J=10.0 Hz,1H), 5.25-5.29 (dd, J=1.5, 17.0 Hz, 1H), 5.80-5.95 (m, 3H), 6.86 (s,1H), 7.02 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.6, 21.2, 21.8, 21.9,22.0, 22.1, 35.6, 47.7, 68.5, 68.9, 72.1, 78.1, 106.9, 118.0, 120.4,123.7, 128.7, 134.2, 149.7, 151.8, 158.8, 170.4, 171.2; LCQ-MS (M+H⁺)calcd for C₂₆H₃₇N₂O₅ 457. found 457; LC-TOF-MS (M+H⁺) calcd forC₂₆H₃₇N₂O₅ 457.27025. found 457.26984.

Example 7

(2R,3R)-2-(Allyloxy)-3-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)-methyl)butane-1,4-diol(11). To a solution of 10 (300 mg, 0.70 mmol) in THF (15 mL) at 0° C.was added LiAlH₄ (55 mg, 1.4 mmol) in several portions. The reactionmixture was allowed to stir at 0° C. for 20 min then carefully quenchedwith H₂O (50 μL). The solvent was removed by rotary evaporation, and thecrude product was purified by flash column chromatography(EtOAc/hexanes, 1:2-1:1) to give 11 (205 mg, 0.60 mmol, 86%) as acolorless oil: ¹H NMR (500 MHz, CDCl₃) δ 2.10 (s, 6H), 2.30-2.38 (br s,1H), 2.39 (s, 3H), 2.83-2.88 (dd, J=4.0, 13.5 Hz, 1H), 2.90-2.94 (dd,J=5.5, 14.0 Hz, 1H), 3.40-3.57 (m, 3H), 3.62-3.67 (m, 2H), 3.74-3.78(dd, J=5.0, 11.5 Hz, 1H), 4.00-4.04 (dd, J=6.0, 12.5 Hz, 1H), 4.10-4.15(dd, J=5.0, 13.5 Hz, 1H), 5.15-5.18 (dd, J=1.5, 11.5 Hz, 1H), 5.24-5.28(dd, J=1.5, 17.5 Hz, 1H), 6.88 (s, 1H), 7.05 (s, 1H); ¹³C NMR (125 MHz,CDCl₃) δ 13.3, 14.4, 21.2, 21.3, 36.0, 43.0, 60.6, 61.8, 61.9, 71.5,77.1, 77.3, 77.6, 81.5, 106.9, 117.4, 120.9, 124.0, 128.7, 135.0, 150.5,151.7, 160.3, 171.4; LCQ-MS (M+H⁺) calcd for C₂₀H₂₉N₂O₃ 345. found 345;LC-TOF-MS (M+H⁺) calcd for C₂₀H₂₉N₂O₃ 345.21782. found 345.21772.

Example 8

2-(((3R,4R)-4-(Allyloxy)-tetrahydrofuran-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine(13). ¹H NMR (500 MHz, CDCl₃) δ 2.07 (s, 3H), 2.09 (s, 3H), 2.75 (s,3H), 3.07 (s, 3H), 3.35-3.45 (m, 1H), 3.79-3.84 (dd, J=6.0, 18.0 Hz,1H), 3.96-4.00 (dd, J=6.0, 12.5 Hz, 1H), 4.04-4.05 (d, J=5.0 Hz, 1H),4.16-4.20 (dd, J=5.5, 12.0 Hz, 1H), 4.24-4.32 (m, 2H), 4.40-4.55 (m,3H), 5.15 (s, 1H), 5.18 (s, 1H), 5.70-5.80 (m, 1H), 6.04 (s, 2H), 7.41(s, 1H), 7.92 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 12.5, 12.6, 22.7,37.3, 37.7, 38.0, 39.7, 57.3, 67.8, 71.7, 110.0, 118.8, 125.5, 126.4,129.3, 133.7, 144.4, 161.2; LCQ-MS (M⁺) calcd for C₂₁H₂₉N₂O₄S 405. found405; LC-TOF-MS (M+H⁺) calcd for C₂₀H₂₇N₂O₂ 405.18425. found 405.18398.

Example 9

2-(((3R,4R)-4-(Allyloxy)-tetrahydrofuran-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine(14). ¹H NMR (500 MHz, CDCl₃) δ 2.09 (s, 6H), 2.40 (s, 3H), 2.85-2.92(m, 2H), 3.09-3.13 (dd, J=5.5, 17.0 Hz, 1H), 3.66-3.81 (dd, J=8.0, 9.5Hz, 1H), 3.82-3.87 (m, 2H), 3.88-3.91 (m, 3H), 4.02-4.06 (dd, J=5.5,13.0 Hz, 1H), 5.16-5.18 (dd, J=1.5, 10.0 Hz, 1H), 5.26-5.29 (dd, J=1.5,17.0 Hz, 1H), 5.85-5.89 (m, 3H), 6.87 (s, 1H), 7.02 (s, 1H); LCQ-MS(M+H⁺) calcd for C₂₀H₂₇N₂O₂ 327. found 327; LC-TOF-MS (M+H⁺) calcd forC₂₀H₂₇N₂O₂ 327.20725. found 327.20770.

Example 10

(2S,3R)-Isopropyl3-(allyloxy)-2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-4-oxobutanoate(16). To a solution of diisopropyl ester 10 (140 mg, 0.31 mmol) intoluene (5 mL) at −78° C. was added dropwise a solution of Dibal-H (1.0M in toluene, 620 μL, 0.62 mmol) along the side of the flask over aperiod of 15 min. The reaction was maintained at −78° C. during theaddition and allowed to react at the same temperature for 7 h. To theresulting solution at −78° C., MeOH (100 μL) was added dropwise alongthe side of the flask to quench the reaction. The reaction mixture waswarmed to −20° C. and poured directly onto a vigorously stirringRochelle's solution (potassium sodium tartrate solution, 5 mL). Theviscous solution was allowed to stir for an additional 30 min thensettled down to two clear phases. The organic layer was separated, andthe aqueous layer was extracted with ether (3×5 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated. The crudeproduct was purified by flash column chromatography (EtOAc/hexanes,1:9-1:4) to give 16 (75 mg, 0.19 mmol, 62%) as a colorless oil: ¹H NMR(500 MHz, CDCl₃) δ 1.11-1.13 (d, J=6.0, 3H), 1.16-1.18 (d, J=6.5, 3H),2.11 (s, 6H), 2.40 (s, 3H), 3.01-3.04 (dd, J=6.5, 14.5 Hz, 1H),3.28-3.33 (dd, J=8.0, 15.0 Hz, 1H), 3.60-3.73 (ddd, J=4.0, 7.0, 11.5 Hz,1H), 3.85-3.86 (dd, J=1.0, 4.5 Hz, 1H), 4.03-4.06 (dd, J=6.0, 13.0 Hz,1H), 4.21-4.25 (dd, J=6.0, 12.5 Hz, 1H), 4.96-4.98 (m, 1H), 5.19-5.22(dd, J=1.5, 10.5 Hz, 1H), 5.24-5.28 (dd, J=2.0, 17.5 Hz, 1H), 5.86-5.91(m, 3H), 6.88 (s, 1H), 7.03 (s, 1H), 9.75-9.77 (d, J=1.0 Hz, 1H); ¹³CNMR (125 MHz, CDCl₃) δ 13.5, 21.2, 22.0, 35.4, 46.8, 69.1, 72.7, 83.1,106.9, 107.0, 118.6, 120.7, 123.7, 128.7, 133.9, 149.9, 151.9, 158.5,171.0, 202.5; LCQ-MS (M+H⁺) calcd for C₂₃H₃₁N₂O₄ 399. found 399;LC-TOF-MS (M+H⁺) calcd for C₂₃H₃₁N₂O₄ 399.22838. found 399.22859.

Example 11

(2S,3R)-Isopropyl3-(allyloxy)-2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-4-hydroxybutanoate(17). ¹H NMR (500 MHz, CDCl₃) δ 1.10-1.30 (m, 6H), 2.10 (s, 6H), 2.40(s, 3H), 2.87-3.20 (m, 3H), 3.40-3.50 (m, 2H), 3.80-4.20 (m, 5H),5.10-5.40 (m, 4H), 5.80-5.96 (m, 3H), 6.88 (s, 1H), 7.03-7.05 (d, J=7.5Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 13.5, 13.6, 21.2, 21.7, 22.0, 23.7,31.6, 23.8, 33.4, 33.5, 45.0, 47.1, 49.5, 69.3, 69.5, 71.3, 71.6, 71.7,71.9, 83.3, 84.0, 84.2, 99.6, 100.2, 101.2, 102.3, 103.7, 104.4, 106.8,107.0, 108.3, 117.4, 117.5, 120.3, 120.4, 123.3, 123.4, 128.7, 134.1,134.5, 134.6, 149.8, 151.9, 159.8, 160.1; LCQ-MS (M+H⁺) calcd forC₂₃H₃₃N₂O₄ 401. found 401; LC-TOF-MS (M+H⁺) calcd for C₂₃H₃₁N₂O₄401.24403. found 401.24336.

Example 12

(3S,4R)-4-(allyloxy)-3-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-tetrahydrofuran-2-ol(18, a mixture of two diastereomers): ¹H NMR (500 MHz, CDCl₃) δ 2.14 (s,6H), 2.40 (s, 3H), 2.85-3.00 (m, 1H), 3.10-3.20 (m, 2H), 3.70-3.90 (m,2H), 3.91-4.07 (m, 2H), 4.08-4.22 (m, 2H), 5.10-5.34 (m, 2H), 5.40 (s,1H), 5.80-6.00 (m, 3H), 6.83-6.95 (m, 1H), 6.96-7.03 (m, 1H); ¹³C NMR(125 MHz, CDCl₃) δ 13.5, 21.2, 21.9, 30.0, 34.1, 34.5, 40.6, 42.1, 68.2,70.2, 71.5, 72.3, 73.6, 79.4, 83.8, 98.1, 100.7, 106.9, 107.0, 117.4,118.2, 120.4, 120.6, 128.7, 134.0, 134.6, 149.8, 149.9, 151.9, 160.4;LCQ-MS (M+H⁺) calcd for C₂₀H₂₆N₂O₃ 343. found 343; LC-TOF-MS (M+H⁺)calcd for C₂₀H₂₆N₂O₃ 343.20217. found 343.20197.

Example 13

(2S,3R)-Isopropyl3-(allyloxy)-4-(benzylamino)-2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)butanoate(19). To a solution of 16 (240 mg, 0.6 mmol) in THF (5 mL) was addedbenzylamine (100 μL, 0.9 mmol) followed by NaHB(OAc)₃ (153 mg, 0.72mmol). The reaction was allowed to stir for an additional 3 h thenpartitioned between EtOAc (100 mL) and brine (50 mL). The aqueous layerwas extracted with EtOAc (50 mL). The combined organic layers were driedover Na₂SO₄ and concentrated. The crude product was purified by flashcolumn chromatography (EtOAc:hexanes, 1:2-1:1) to give 19 (270 mg, 0.55mmol, 92%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 0.99-1.01 (d,J=6.5 Hz, 3H), 1.09-1.11 (d, J=6.5 Hz, 3H), 2.13 (s, 6H), 2.37 (s, 3H),2.76-2.85 (ddd, J=4.5, 5.0, 12.5, Hz, 1H), 2.98-3.08 (ddd, J=5.5, 14.0,15.5, Hz, 1H), 3.49-3.52 (m, 1H), 3.81 (s, 2H), 3.82-3.89 (m, 1H),4.04-4.08 (dd, J=6.0, 12.5, Hz, 1H), 4.09-4.12 ((dd, J=5.5, 13.0, Hz,1H), 4.86-4.89 (m, 1H), 5.13-5.15 (dd, J=1.0, 10.0, Hz, 1H), 5.23-5.28(dd, J=1.5, 17.0, Hz, 1H), 5.86-5.91 (m, 3H), 6.85 (s, 1H), 7.00 (s,1H), 7.20-7.27 (m, 2H), 7.27-7.35 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ13.6, 21.2, 21.8, 21.9, 35.1, 47.6, 49.9, 54.0, 68.0, 71.4, 79.4, 106.8,117.2, 120.3, 123.4, 127.2, 128.4, 128.6, 128.8, 134.9, 140.4, 149.5,151.7, 159.4, 173.0; LCQ-MS (M+H⁺) calcd for C₃₀H₄₀N₃O₃ 490. found 490;LC-TOF-MS (M+H⁺) calcd for C₃₀H₄₀N₃O₃ 490.30697. found 490.30644.

Example 14

(2R,3R)-3-(Allyloxy)-4-(benzylamino)-2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)butan-1-ol(20). To a solution of 19 (400 mg, 0.82 mmol) in THF (20 mL) at 0° C.was added LiAlH₄ (48 mg, 1.2 mmol) in several portions. The reactionmixture was allowed to stir at 0° C. for an additional 10 min thenquenched with H₂O (25 μL). The solvent was removed by rotaryevaporation, and the crude product was purified by flash columnchromatography (EtOAc:hexanes, 2:1-4:1) to give 20 (280 mg, 0.66 mmol,80%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 2.12 (s, 6H), 2.39(s, 3H), 2.64-2.67 (dd, J=2.0, 12.0 Hz, 1H), 2.70-2.90 (m, 2H),2.98-3.03 (dd, J=5.5, 12.5, Hz, 1H), 3.40-3.44 (dd, J=3.0, 11.5 Hz, 1H),3.56-3.58 (dd, J=3.0, 6.0 Hz, 1H), 3.65-3.69 (dd, J=7.5, 11.5 Hz, 1H),3.76-3.79 (d, J=13.0 Hz, 1H), 3.83-3.86 (d, J=13.0 Hz, 1H), 3.90-3.94(dd, J=5.0, 12.5 Hz, 1H), 3.99-4.03 (dd, J=5.5, 12.5 Hz, 1H), 5.15-5.17(dd, J=1.0, 10.5 Hz, 1H), 5.23-5.27 (dd, J=1.0, 18.5 Hz, 1H), 5.80-5.96(m, 3H), 6.86 (s, 1H), 6.99 (s, 1H), 7.24-7.40 (m, 5H); ¹³C NMR (125MHz, CDCl₃) δ 13.5, 21.2, 37.7, 46.4, 49.5, 54.0, 60.8, 70.9, 79.4, 98,9, 106.9, 117.2, 120.4, 123.7, 127.6, 128.6, 128.7, 128.9, 135.0, 139.2,149.8, 151.8, 160.6; LCQ-MS (M+H⁺) calcd for C₂₇H₃₆N₃O₂ 434. found 434;LC-TOF-MS (M+H⁺) calcd for C₂₇H₃₆N₃O₂ 434.28075. found 434.28071.

Example 15

2-(((3R,4R)-4-(Allyloxy)-1-benzylpyrrolidin-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine(2). To a solution of 20 (70 mg, 0.16 mmol) in CH₂Cl₂ (2.0 mL) at roomtemperature was added MsCl (15 μL, 0.19 mmol). After 2 min,triethylamine (34 μL, 0.24 mmol) was added dropwise as a solution inCH₂Cl₂ (340 μL). The reaction was allowed to stir for another 2 min andconcentrated by rotary evaporation. The crude material was purified byflash column chromatography (EtOAc:hexanes, 2:1-4:1) to give 2 (66 mg,0.16 mmol, 100%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 2.12 (s,6H), 2.38 (s, 3H), 2.38-2.43 (m, 1H), 2.53-2.56 (dd, J=3.0, 10.0 Hz,1H), 2.77-2.80 (dd, J=7.5, 8.0 Hz, 1H), 2.80-2.91 (m, 2H), 3.08-3.13 (m,2H), 3.79-3.83 (dd, J=5.5, 13.0 Hz, 1H), 3.97-3.99 (br s, 2H), 5.14-5.16(dd, J=1.0, 10.0 Hz, 1H), 5.23-5.26 (dd, J=1.0, 17.0 Hz, 1H), 5.80-5.89(m, 1H), 5.89 (s, 2H), 6.84 (s, 1H), 7.00 (s, 1H), 7.20-7.40 (m, 5H);¹³C NMR (125 MHz, CDCl₃) δ 13.5, 21.2, 36.2, 42.5, 58.4, 60.2, 61.0,70.9, 79.1, 98.9, 106.8, 116.7, 120.1, 123.4, 127.1, 128.5, 128.7,128.9, 135.2, 149.4, 151.8, 161.3; LCQ-MS (M+H⁺) calcd for C₂₇H₃₄N₃O416. found 416; LC-TOF-MS (M+H⁺) calcd for C₂₇H₃₄N₃O 416.27019. found416.26956.

While the principles of this invention have been described in connectionwith certain embodiments, it should be understood clearly that thesedescriptions are presented only by way of example and are not intendedto limit, in any way, the scope of this invention. For instance, themethodologies of this invention can be applied more specifically to thesynthesis of a range of pyrrolidine compounds wherein ahaloalkylheterocyclic starting material is substituted with anon-heterocyclic starting material (e.g., benzyl bromide or aphenyl-substituted benzyl bromide as can be prepared according to Scheme2) for use in the reaction of Table 1, en route to a correspondingnon-heterocyclyl-substituted pyrrolidine compound. Likewise, alone or inconjunction with the preceding, the present methodologies can bemodified as would be understood by those skilled in the art to providevarious non-allylated compounds. For example, with reference to Scheme3, use of benzyl bromide, a phenyl-substituted benzyl bromide or abromomethylheterocycle compound can be used (instead of allylbromide) enroute to the corresponding benzyl-, phenyl-substituted benzyl- ormethylheterocyclyl-substituted pyrrolidine compound.

1. A compound of a formula

wherein R₁ is selected from C(O)OR′₁, CH₂OH and CH₂SO₃CH₃ moieties,where R′₁ is selected from the C₁-about C₆ alkyl and C₁-about C₆substituted alkyl moieties; R₂ is selected from C₁-about C₆ alkyl andC₁-about C₆ substituted alkyl moieties; R₃ is selected from H and alkylmoieties; and R₄ is selected from H, amino and protected amino moieties,and a salt thereof.
 2. The compound of claim 1 wherein R₃ is an alkylmoiety, and R₄ is a 2,5-dimethylpyrrol-1-yl moiety.
 3. The compound ofclaim 1 selected from (2S,3R) and (2R,3S) diastereomers.
 4. The compoundof claim 1 wherein R₂ is a benzyl moiety.
 5. The compound of claim 4wherein R₁ is a CH₂SO₃CH₃ moiety, said compound mesylated to promoteintramolecular cyclization.